1.
Biomarkers in Sepsis
Utility or Futility?
Dr Andrew Ferguson
Consultant in Intensive Care Medicine and Anaesthesia
Craigavon Area Hospital

2.
Why give this your attention?
• Microbes – the WMDs in your ICU
• Sepsis is the main killer of general ICU patients
• Anything that helps you beat it is good news
• We need better diagnostic & prognostic tools

3.
The clock is ticking - the first 12 hours…
Funk and Kumar, Crit Care Clinics 2011; 53-76.
For first 12 hours, 1% mortality per 5
minute delay

4.
Early antibiotics
Szczepura A, Osipenko L. Point of Care Diagnostics for Sepsis: Health Economic Considerations. Available at https://connect.innovateuk.org/documents/3187680/3710018/Sepsis-TSB-27-07-12-Economic-slides.pdf/d805c6a6-ecdf-
43c7-ac60-9e4da9d046fd;jsessionid=481FF37BC0ECFA0D6D41EC7474D20822.2

5.
Early detection is paramount

6.
Conventional detection of sepsis
• 2 main strategies…
• Detection of bacterial pathogen
– Slow and all too often negative
• Detection of host response
– NEWS for fever, tachycardia, tachypnoea
– “Conventional” lab tests (WBC, CRP etc)
– The ICU eyeball test
1
2

7.
What’s wrong with that?
• Physiological reserve determines presentation
• Physiological reserve determines trajectory
• Misdiagnosis in patients with comorbidity
• Recognition of severity is biased
• Prognostication is weakened
• There might not be an ICU eyeball

8.
Enter the goose and the…

9.
The biomarker paradigm…
• Sepsis leads to
– Inflammation
– Coagulation
– Tissue damage and repair
• The sicker you are, the greater the changes
• We can identify biomarkers for these processes
• We can measure these biomarkers
• We can stratify severity based on biomarker levels
• We can prognosticate based on biomarker levels

10.
Damage Associated Molecular Patterns

11.
Pathogen Associated Molecular Patterns

12.
Biomarker Candidates
• Multiple, and growing all the time
• Some more common in the literature
• Linked to the main underlying processes
– Inflammation
– Coagulation
– Tissue damage
– Tissue repair

13.
Examples
• Acute phase proteins
– CRP
– Procalcitonin
– Pentraxin 3 (PTX3)
– Lipopolysaccharide binding protein (LBP)
• Cytokines & chemokines
– IL-1RA, IL-1 , IL-2, IL-6, MCP-1
– TNF- , TNFR1/2
– HMGBP1
• Cell surface markers
– Soluble CD14 (presepsin)
– Neutrophil CD64 index (CD64in)
– mHLA-DR (monocyte HLA-DR levels)
– CD-163
• Receptor markers
– VEGF
– Soluble VEGF-receptor 1 (sFLT)
– Soluble urokinase plasminogen activator (suPAR)
– sTREM-1
– RAGE (soluble receptor for advanced glycation
end products)
• Coagulation
– Activated partial thromboplastin time
(aPTT) waveform analysis
– Protein C receptor
– Thrombomodulin
• Endothelial damage
– Heparin binding protein
– E-selectin
– Neopterin
– ICAM-1, VCAM-1
– Angiopoietin-1 and -2
– Syndecan-1 and -2
• Vasodilation
– Copeptin (AVP precursor)
• Cell damage
– MicroRNA
– Microparticles
• Cell repair
– Procollagen III amino propeptide

14.
Questions to be answered
• Does the biomarker aid diagnosis?
• Does it provide additional prognostic info?
– For outcome
– For progression/decline
• Better than the ICU eye?
• Better than scoring systems?

15.
Procalcitonin
• Bacterial infections
– > ubiqitous CALC-1 gene expression
– > release of PCT from all parenchymal tissues
– Procalcitonin (PCT) increases after 2-3 hours after
induction e.g. by endotoxin
– Falls with successful treatment

16.
Procalcitonin

17.
Procalcitonin

18.
Procalcitonin

19.
Procalcitonin

20.
Procalcitonin in IFI
“Fungi-related sepsis, even severe sepsis or septic shock, does not necessarily elicit a
substantial increase in serum PCT”

21.
Procalcitonin and prognosis

22.
Where next?

23.
Cytokines
Faix JD. Crit Rev Clin Lab Sci, 2013; 50(1): 23–36

24.
Cytokines - IL-6
• Can be reliably measured
• Not specific for sepsis (hence not diagnostic)
• PROGNOSTIC tool
– Increased mortality as level rises
– Increased risk of progression to severe sepsis/shock

25.
Chemokines
• IL-8
• MCP-1 (monocyte chemoattractant protein 1)
• IL-8 can be used as diagnostic tool in sepsis
• MCP-1 can be used as PROGNOSTIC tool
– Mortality risk

26.
Leukocyte activation markers
Prognostic
Faix JD. Crit Rev Clin Lab Sci, 2013; 50(1): 23–36

27.
Pentraxin 3
• Pentraxins are liquid-phase PAMP receptors
• “Short” pentraxins include CRP (bet you didn’t know
that!) as is serum amyloid P component (SAP)
• Pentraxin-3 involved in:
– complement activation
– pathogen opsonisation
– self versus modified-self versus non-self discrimination

28.
Pentraxin-3

29.
28-day progression

30.
• Detects sepsis
– AUC 0.96
• Predicts progression
– AUC 0.87
– Sens 82% Spec 89% at 12ng/ml
• Did not predict mortality

31.
Is it really that simple?

32.
Obviously NOT!

33.
The Future

34.
Fatty acid 2 oxidation issue in non-survivors v survivors related to carnitine shuttle
(defective fatty acid transfer into mitochondria). Detectable at presentation.

35.
Microparticles?
• Small vesicles shed from membranes of
apoptotic and stress-activated cells
– Endothelial cells, RBCs, monocytes, platelets

36.
Conclusion
• Biomarkers have utility and potential
• Earlier detection of disease
• Earlier detection of high risk sub-groups
• Earlier recognition of treatment success
• Earlier de-escalation
• Adjunctive prognostication